Glaucoma is a disease of the eye characterized by increased intraocular pressure. The intraocular pressure (IOP) in the hypertensive eye causes atrophy and excavation of the ocular nerve thereby producing the visual defects associated with glaucoma. If untreated, increased IOP may cause permanent visual defects or even blindness. It is known that IOP may be affected by application of various adrenergic agents which are active on the sympathoadrenal system. Adrenergic agents exert their activity by interaction with adrenal receptors (adrenoceptors). The agents may be characterized by their activity, i.e. as stimulating agents (agonists) or blocking agents (antagonists), and by the specific type of adrenoceptors upon which they act.
Adrenoceptors are of two primary types: alpha and beta. Based upon the selectivity of the receptors for a series of agonists and antagonists, the alpha adrenoceptors are divided into subtypes, designated alpha.sub.1, alpha.sub.2, and more recently, alpha.sub.3.
Alpha.sub.1 and alpha.sub.2 adrenoceptors were originally described by their anatomical location. The alpha.sub.1 and alpha.sub.2 adrenoceptors are usually located on post- and pre-junctional sites, respectively. Ever increasing evidence caused a revision of this classification. The alpha.sub.1 adrenoceptor is now described as prazosin-sensitive and the alpha.sub.2 adrenoceptor as rauwolscine-sensitive.
The existence of a third adrenoceptor is supported by a large amount of experimental evidence. Experiments using selective agonists and antagonists of both alpha.sub.1 and alpha.sub.2 adrenoceptors demonstrated that in addition to the classical post-junctional alpha.sub.1 adrenoceptor, an additional post-junctional adrenoceptor was present which closely resembled the pre-junctional alpha.sub.2 adrenoceptor which had been characterized in many systems. The concept of post-junctional alpha.sub.2 adrenoceptors mediating prazosin-resistant vasoconstriction has been proposed by Timmermans, et al., Nauyn-Schmiedeberg's Arch. Pharmacol., 310, 189 (1979), and Ruffolo, Pharm. Biochem. and Behav., 22, 827 (1985). It has now been discovered that the prazosin-insensitive post-junctional adrenoceptor is pharmacologically distinct from the pre-junctional alpha.sub.2 andrenoceptor. (Ruffolo, R., et al., Nauyn-Schmiedeberg's Arch. Pharmacol. 336, 415-418. (1987)) This post-junctional, prazosin-insensitive receptor is referred to as the alpha.sub.3 adrenoceptor.
At this juncture, it should be noted that alpha agonists and alpha antagonists appear to preferentially stimulate or block each type of adrenoceptor with varying degrees of specificity rather than exclusively stimulating or blocking one adrenoceptor sub-type. For example, clonidine preferentially stimulates alpha.sub.2 adrenoceptor.gtoreq.alpha.sub.3 adrenoceptor&gt;&gt;alpha.sub.1 adrenoceptor and is therefore characterized as an alpha.sub.2 agonist. As a further example, an alpha.sub.3 antagonist of the present invention, 9-(3 methyl-2-butenyloxy)-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3 benzazepine, blocks the alpha.sub.3 adrenoceptor.gtoreq.alpha.sub.1 adrenoceptor&gt;&gt;alpha.sub.2 adrenoceptor and is therefore characterized as an alpha.sub.3 adrenoceptor antagonist.
Topically administered alpha agonists which are efficacious in lowering IOP are part of current ocular hypertension therapy, including glaucoma therapy. However, some undesirable side effects are associated with the use of these compounds for treatment of ocular hypertension. For example, some alpha agonists are known to cause significant and undesirable cardiovascular (systemic) hypotension and mydriasis (pupil dilation). These side effects are mediated by central nervous system alpha.sub.2 adrenoceptors and ocular alpha.sub.1 adrenoceptors, respectively.
However, based on the known efficacy of some alpha.sub.2 agonists for treatment of ocular hypertension, efforts are being made to develop more selective alpha.sub.2 adrenoceptors which remain localized in the ocular environment and have less side effects and to develop methods and compositions to potentiate the effect of the agonist while reducing the side effects associated with its use.
To develop either more selective alpha.sub.2 agonists or potentiating compositions and methods, it is important to focus on some factors which mediate the efficacy of alpha.sub.2 agonists for lowering IOP. The ocular hypotensive activity of an alpha.sub.2 agonist is dependent on several factors: (a) the degree of specificity for the alpha.sub.2 adrenoceptor, (b) the dosage of the alpha.sub.2 agonist and (c) the drug delivery method. The dosage of conventional alpha.sub.2 agonists needed to achieve a desired therapeutic ocular hypotensive effect may cause various undesirable side effects, such as cardiovascular hypotension and mydriasis. Depending on the patient, other localized or systemic adverse indications, reactions, or toxicity may result. Accordingly, a need exists for compositions and/or methods which enable either (a) improved therapeutic effect per unit dose of the alpha.sub.2 agonist and/or (b) use of smaller doses of the alpha.sub.2 agonist.
The present invention is directed to the discovery that co-administrating an alpha.sub.3 antagonist with an alpha.sub.2 agonist directly to the eye potentiates the IOP lowering effect of the alpha.sub.2 agonist. Co-administrating an alpha.sub.3 antagonist mitigates, reduces or eliminates undesirable side effects associated with conventional alpha.sub.2 agonist therapy for treatment of ocular hypertension and enables treatment with lower alpha.sub.2 agonist dosages. In addition, co-administration of an alpha.sub.2 agonist with an alpha.sub.3 antagonist enables equivalent or improved therapeutic treatment of ocular hypertension as compared to using equivalent or higher dosages of the alpha.sub.2 agonist alone.
Alpha.sub.3 antagonists, such as those disclosed herein, are known to be useful in treatment of cardiovascular hypertension as disclosed in U.S. Pat. No. 4,683,229 by DeMarinis, et. al. However, alpha.sub.3 antagonists have never been used for treatment of ocular hypertension.